Optogeneticcontrolovertransgeneexpressionforthetherapyofbrainandspine Abstract Genemodifiedstemcellsareapowerfultoolfortheproductionofsecretabletherapeuticproteinsinthebody.Yet, thereisavalidconcernovertheirsafetysincethereisnowaytocontrolthemoncetheyhavebeentransplanted.We proposetoutilizeoptogeneticcontroloftranscription(ORT)toexternallycontrolsecretionofthetherapeuticprotein usingredlight.ORTwouldimprovetheefficacyandsafetyofthetherapybyrepeatedremoteactivationoftransgene synthesiswithredlightdeliverednoninvasively.Foraspecificdiseaseapplication,weproposetouseintrathecally deliveredORTdrivenstemcellstoproduceantiinflammatoryantiTNFhybridantibodiesinthesubarachnoidcavity forthetherapyofneuroinflammationinthebrain.TheORToptionwouldallowustoexternallyinduceproductionof the antiinflammatory antibody using red light as needed. At this initial phase of the project, we propose the conceptualevaluationoftheORTsystemgeneticallyembeddedintobonemarrowstemcells.Thistestingisproposed incellculture(Aim1)andthemousecerebralsubarachnoidcavity(Aim2).Theproposedmethodaimstoimprovethe safety and efficiency of the therapy of chronic CNS disorders with episodic neuroinflammatory components by providingthebenefitofremotecontrolofthetiminganddosageofthetherapy.